P1017: REDUCTIONS IN INDOLENT SYSTEMIC MASTOCYTOSIS BIOMARKER BURDEN WITH AVAPRITINIB IN THE REGISTRATIONAL, DOUBLE-BLIND PLACEBO-CONTROLLED PIONEER TRIAL
Authors: Jason Gotlib, Mariana Castells, Hanneke Oude Elberink, Frank Siebenhaar, Karin Hartmann, Sigurd Broesby-Olsen, Tracy I. George, Jens Panse, Ivan Alvarez-Twose, Deepti Radia, Tsewang Tashi, Cristina Bulai Livideanu, Vito Sabato, Paul Van Daele, Sonia Cerquozzi, Ingunn Dybedal, Andreas Reiter, Celalettin Ustun, Philippe Schafhausen, Prithviraj Bose, Daniel J. Deangelo, Lindsay Rein, Pankit Vachhani, Massimo Triggiani, Mark Rafferty, Nauman Butt, Stephen Oh, Friederike Wortmann, Johanna Ungerstedt, Minakshi Taparia, Andrew T. Kuykendall, Cecilia Arana Yi, Mattias Mattsson, William Shomali, Matthew Giannetti, Ilda Bidollari, Hui-Min Lin, Robyn Scherber, Maria Roche, Cem Akin, Marcus Maurer
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Indolent systemic mastocytosis (ISM), a clonal mast cell (MC) disease primarily driven by the KIT D816V mutation, is characterized by abnormal MC accumulation and activation. To date, no therapies have demonstrated disease modification in a controlled trial. PIONEER (NCT03731260) is a randomized, double-blind, placebo-controlled study of avapritinib, a potent, highly selective, oral inhibitor of KIT D816V in patients with symptomatic ISM despite best supportive care (BSC). Recently reported findings (Castells M, et al. J Allergy Clin Immunol. 2023;151(2):AB204) from this trial demonstrated that patients treated with avapritinib achieved significantly greater improvement in patient-reported total symptom scores (TSS) vs placebo after 24 weeks of treatment. Aims: To assess the impact of avapritinib vs placebo on objective biomarkers of MC burden in patients with ISM. Methods: Adult patients with ISM were randomly assigned 2:1 to avapritinib 25 mg QD + BSC (“avapritinib”) or placebo + BSC (“placebo”) groups and stratified by baseline serum tryptase (<20 ng/mL vs ≥20 ng/mL). Endpoints included ≥50% reduction in serum tryptase, bone marrow (BM) MC burden, and KIT D816V variant allele frequency (VAF) in peripheral blood (PB) at 24 weeks. One-sided P-values are reported. Additional analyses included reduction of serum tryptase to <20 ng/mL, total clearance of BM MC aggregates, and reduction of KIT D816V VAF to undetectable levels (<0.02%). Patient-reported outcomes included TSS evaluated using the ISM symptom assessment form (ISM-SAF ©2018). Safety was also assessed. Results: Baseline characteristics for patients in the avapritinib (n=141) and placebo (n=71) groups were similar. In the avapritinib group, baseline median (range) serum tryptase, BM MC burden, and KIT D816V VAF in PB were 38.4 ng/mL (3.6–256.0), 7.0% (1.0–50.0), and 0.4% (0.02–41.3), and in the placebo group were 43.7 ng/mL (5.7–501.6), 7.0% (1.0–70.0), and 0.3% (0.02–36.7). At week 24, a significantly greater proportion of patients in the avapritinib group vs placebo group (all P<0.0001) achieved ≥50% reductions in serum tryptase levels (54% [76/141] vs 0% [0/71]), BM MC burden (53% [56/106] vs 23% [13/57]), and KIT D816V VAF (68% [80/118] vs 6% [4/63]). Reduction of serum tryptase to <20 ng/mL from ≥20 ng/mL at baseline was observed in 54% (58/107; <11.4 ng/mL, n=29; 11.4–<20 ng/mL, n=29) in the avapritinib group vs 2% (11.4–<20 ng/mL, n=1/50) in the placebo group. Mean percent change (SD) BM MC burden was greater with avapritinib vs placebo (–11.3% [84.1] vs 0.4% [69.1]). Of patients with BM MC aggregates at baseline, total clearance of BM MC aggregates was three times more common in the avapritinib group than placebo (36% [n=33/91] vs 12% [n=6/50]). Of patients with detectable KIT D816V VAF at baseline, 11% (n=12/109) in the avapritinib group had undetectable KIT D816V VAF at 24 weeks vs 6% (n=3/54) in the placebo group. In the primary endpoint analysis, the avapritinib group had significantly greater mean change (95% CI) in TSS at 24 weeks vs placebo (–15.6 [–18.6, –12.6] vs –9.2 [–13.1, –5.2]; P=0.003). Avapritinib was well tolerated with a safety profile comparable to placebo. Summary/Conclusion: In patients with ISM, avapritinib 25 mg QD significantly reduced objective biomarkers of MC burden, notably improved symptoms, and was well-tolerated. These results support avapritinib as a potentially disease-modifying therapy for patients with ISM.Keywords: c-kit, Systemic mastocytosis, Tyrosine kinase inhibitor